Meta-Analysis

. 2023 Oct;11(10):743-754.

doi: 10.1016/S2213-8587(23)00227-9. Epub 2023 Sep 8.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Yanning Xu¹, Arash Derakhshan², Ola Hysaj³, Lea Wildisen³, Till Ittermann⁴, Alessandro Pingitore⁵, Nazanin Abolhassani³, Marco Medici⁶, Lambertus A L M Kiemeney⁷, Niels P Riksen⁸, Robin P F Dullaart⁹, Stella Trompet¹⁰, Marcus Dörr¹¹, Suzanne J Brown¹², Börge Schmidt¹³, Dagmar Führer-Sakel¹⁴, Mark P J Vanderpump¹⁵, Axel Muendlein¹⁶, Heinz Drexel¹⁷, Howard A Fink¹⁸, M Kamran Ikram¹⁹, Maryam Kavousi²⁰, Connie M Rhee²¹, Isabela M Bensenor²², Fereidoun Azizi²³, Graeme J Hankey²⁴, Massimo Iacoviello²⁵, Misa Imaizumi²⁶, Graziano Ceresini²⁷, Luigi Ferrucci²⁸, José A Sgarbi²⁹, Douglas C Bauer³⁰, Nick Wareham³¹, Kristien Boelaert³², Stephan J L Bakker⁹, J Wouter Jukema³³, Bert Vaes³⁴, Giorgio Iervasi⁵, Bu B Yeap³⁵, Rudi G J Westendorp³⁶, Tim I M Korevaar², Henry Völzke⁴, Salman Razvi³⁷, Jacobijn Gussekloo³⁸, John P Walsh³⁹, Anne R Cappola⁴⁰, Nicolas Rodondi⁴¹, Robin P Peeters², Layal Chaker⁴²; Thyroid Studies Collaboration

Affiliations

¹ Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
² Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands.
³ Institute of Primary Health Care, University of Bern, Bern, Switzerland.
⁴ Institute for Community Medicine, Clinical-Epidemiological Research, University Medicine Greifswald, Greifswald, Germany; German Centre for Cardiovascular Research, Partner site Greifswald, Greifswald, Germany.
⁵ National Research Council Institute of Clinical Physiology, Pisa, Italy.
⁶ Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
⁷ Radboud University Medical Center, Radboud Institute for Health Sciences, Department for Health Evidence, Nijmegen, Netherlands.
⁸ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
⁹ Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
¹⁰ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands.
¹¹ German Centre for Cardiovascular Research, Partner site Greifswald, Greifswald, Germany; Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
¹² Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
¹³ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁴ Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁵ The Physicians' Clinic, London, England, UK.
¹⁶ Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria.
¹⁷ Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Drexel University College of Medicine, Philadelphia, PA, USA.
¹⁸ Geriatric Research Education and Clinical Center, VA Healthcare System, Minneapolis, MN, USA; Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
¹⁹ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands.
²⁰ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
²¹ Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange, CA, USA.
²² Department of Internal Medicine, University of São Paulo Medical School, São Paulo, Brazil.
²³ Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
²⁴ The University of Western Australia, Perth, WA, Australia; Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.
²⁵ Cardiology Unit, Cardiothoracic Department, University Polyclinic Hospital of Bari, Bari, Italy.
²⁶ Department of Clinical Studies, Radiation Effects Research Foundation, Nagasaki, Japan.
²⁷ Department of Medicine and Surgery, Unit of Internal Medicine and Onco-Endocrinology, University Hospital of Parma, Parma, Italy.
²⁸ Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
²⁹ Division of Endocrinology and Metabolism, Faculdade de Medicina de Marília, Marília, Brazil.
³⁰ Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
³¹ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.
³² Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
³³ Department of Cardiology, Leiden University Medical Center, the Netherlands; Netherlands Heart Institute, Utrecht, Netherlands.
³⁴ Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Leuven, Belgium.
³⁵ The University of Western Australia, Perth, WA, Australia; Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, WA, Australia.
³⁶ Department of Public Health, University of Copenhagen, Copenhagen, Denmark; Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.
³⁷ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
³⁸ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, the Netherlands.
³⁹ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; The University of Western Australia, Perth, WA, Australia.
⁴⁰ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
⁴¹ Institute of Primary Health Care, University of Bern, Bern, Switzerland; Department of General Internal Medicine, Inselspital, University of Bern, Switzerland.
⁴² Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands. Electronic address: l.chaker@erasmusmc.nl.

PMID: 37696273
PMCID: PMC10866328
DOI: 10.1016/S2213-8587(23)00227-9

Meta-Analysis

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Yanning Xu et al. Lancet Diabetes Endocrinol. 2023 Oct.

. 2023 Oct;11(10):743-754.

doi: 10.1016/S2213-8587(23)00227-9. Epub 2023 Sep 8.

Authors

Affiliations

¹ Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
² Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands.
³ Institute of Primary Health Care, University of Bern, Bern, Switzerland.
⁴ Institute for Community Medicine, Clinical-Epidemiological Research, University Medicine Greifswald, Greifswald, Germany; German Centre for Cardiovascular Research, Partner site Greifswald, Greifswald, Germany.
⁵ National Research Council Institute of Clinical Physiology, Pisa, Italy.
⁶ Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
⁷ Radboud University Medical Center, Radboud Institute for Health Sciences, Department for Health Evidence, Nijmegen, Netherlands.
⁸ Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
⁹ Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
¹⁰ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands.
¹¹ German Centre for Cardiovascular Research, Partner site Greifswald, Greifswald, Germany; Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
¹² Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
¹³ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁴ Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁵ The Physicians' Clinic, London, England, UK.
¹⁶ Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria.
¹⁷ Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Drexel University College of Medicine, Philadelphia, PA, USA.
¹⁸ Geriatric Research Education and Clinical Center, VA Healthcare System, Minneapolis, MN, USA; Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
¹⁹ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands.
²⁰ Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
²¹ Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange, CA, USA.
²² Department of Internal Medicine, University of São Paulo Medical School, São Paulo, Brazil.
²³ Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
²⁴ The University of Western Australia, Perth, WA, Australia; Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.
²⁵ Cardiology Unit, Cardiothoracic Department, University Polyclinic Hospital of Bari, Bari, Italy.
²⁶ Department of Clinical Studies, Radiation Effects Research Foundation, Nagasaki, Japan.
²⁷ Department of Medicine and Surgery, Unit of Internal Medicine and Onco-Endocrinology, University Hospital of Parma, Parma, Italy.
²⁸ Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
²⁹ Division of Endocrinology and Metabolism, Faculdade de Medicina de Marília, Marília, Brazil.
³⁰ Departments of Medicine, Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
³¹ Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.
³² Institute of Applied Health Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
³³ Department of Cardiology, Leiden University Medical Center, the Netherlands; Netherlands Heart Institute, Utrecht, Netherlands.
³⁴ Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Leuven, Belgium.
³⁵ The University of Western Australia, Perth, WA, Australia; Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, WA, Australia.
³⁶ Department of Public Health, University of Copenhagen, Copenhagen, Denmark; Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.
³⁷ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
³⁸ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, the Netherlands.
³⁹ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; The University of Western Australia, Perth, WA, Australia.
⁴⁰ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
⁴¹ Institute of Primary Health Care, University of Bern, Bern, Switzerland; Department of General Internal Medicine, Inselspital, University of Bern, Switzerland.
⁴² Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands. Electronic address: l.chaker@erasmusmc.nl.

PMID: 37696273
PMCID: PMC10866328
DOI: 10.1016/S2213-8587(23)00227-9

Abstract

Background: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT₄) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT₄ based on the risk of cardiovascular disease and mortality.

Methods: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT₄, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT₄, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576.

Findings: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT₄ with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT₄ in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT₄ greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT₄ greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality.

Interpretation: There was a J-shaped association of FT₄ with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT₄ and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT₄ greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes.

Funding: None.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests TIMK reports personal fees from IBSA, Meck, Berlin-Chemie, and Quidel; is an unpaid co-chair of the American Thyroid Association guidelines on thyroid and pregnancy. BBY reports grants from National Health and Medical Research Council, Fremantle Hospital Medical Research Foundation, and Ada Bartholomew Medical Research Trust. NR reports a grant from the Swiss National Science Foundation. SR reports a grant for an investigator-initiated trial by Merck; manufacturer of levothyroxine and speaker fees from Merck, Abbott Pharmaceuticals, IBSA (makers of levothyroxine). JWJ reports research grants from or was a speaker (with or without lecture fees) at (Continuing Medical Education accredited) meetings sponsored or supported by Abbott, Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Edwards Lifesciences, GE Healthcare, Johnson and Johnson, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme. DCB reports research grants from the National institutes of Health. DF reports a research grant from DFG SFB TR 296 LOCOTACT. RGJW reports a research grant from the Novo Nordisk Foundation Challenge Programme (NNF17OC0027812). All other authors declare no competing interests.

Figures

**Figure 1:**
PRISMA flow chart of included cohorts

**Figure 2:**
Association of FT4 percentiles with composite outcome, all-cause mortality, CVD mortality, and CVD events. Hazard ratios were plotted against FT4 percentiles taking the FT4 percentile with the lowest hazard ratio as the reference. Hazard ratios were adjusted for age and sex. The shaded band represents the 95% confidence interval. FT4=free thyroxine. CVD=cardiovascular disease. P denotes the p value for the association of exposure with the outcome. No. of events/No. of participants: composite outcome, 14904/51081 (29.2%); all-cause mortality, 21873/94295 (23.2%); CVD mortality, 6866/82926 (8.3%); CVD events, 9990/51081 (19.6%).

**Figure 3:**
Association of quintiles of TSH and FT4 with the composite outcome, all-cause mortality, CVD mortality, and CVD events. Hazard ratios were adjusted for age and sex. TSH=thyroid stimulating hormone. FT4=free thyroxine. CVD=cardiovascular disease.

**Figure 4:**
Association between FT4 percentiles and composite outcome stratified by age categories. Hazard ratios were plotted against FT4 percentiles taking the FT4 percentile with the lowest hazard ratio as reference. Hazard ratios were adjusted for age and sex. The shaded band represents the 95% confidence interval. FT4=free thyroxine. P denotes the p value for the association of exposure with the outcome. No. of events/No. of participants: age 18–49, 889/14659 (6.1%); age 50–69, 5374/22176 (24.2%); age 70–79, 6391/11007 (58.1%); age ≥80, 2250/3239 (69.5%).

**Figure5:**
Absolute ten-year risk of the composite outcome by FT4 percentiles stratified by age and sex. FT4=free thyroxine. No. of events/No. of participants: women aged <70 years 2659/20401 (13.0%), men aged <70 years 3604/16434 (21.9%), women aged ≥70 years 3720/5828 (63.8%), men aged ≥70 years 4921/8418 (58.5%).

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Comment in

Is it time to re-assess the development of thyroid function reference ranges?
Pearce EN. Pearce EN. Lancet Diabetes Endocrinol. 2023 Oct;11(10):711-712. doi: 10.1016/S2213-8587(23)00257-7. Epub 2023 Sep 8. Lancet Diabetes Endocrinol. 2023. PMID: 37696274 No abstract available.

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The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Affiliations

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

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Grants and funding

LinkOut - more resources

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